Degraded myelin is associated with cold hypersensitivity in paclitaxel-induced peripheral neuropathy

Cold allodynia is a debilitating symptom of chemotherapy-induced peripheral neuropathy (CIPN), a side effect of many chemotherapeutics, including paclitaxel (PTX). CIPN is highly prevalent and can lead to cessation of chemotherapy, threatening cancer patient survival. PTX induces cold-evoked pain in 60% of CIPN patients and this pain is a predictor for more severe neuropathy. Cold is transduced by primary sensory neurons in dorsal root ganglia (DRG). PTX can induce maladaptive changes in gene expression that lead to dysregulated nociceptor function. Previous work examining PTX-induced transcriptional changes have been unable to isolate mechanisms associated with pathological cold pain. The epigenetic changes that underlie long- lasting transcriptional changes in PTX induced persistent cold hypersensitivity are not known. Following three consecutive cycles of PTX, we find that mice continue to exhibit cold hypersensitivity for a minimum of four weeks following the resolution of PTX-induced mechanical hypersensitivity. This exclusive cold hypersensitivity phenotype allows us to examine the mechanisms that specifically underlie pathological cold pain. During this period of PTX-induced cold hypersensitivity, we found decreased expression of genes whose expression is necessary for myelin sheath formation and maintenance, degraded myelin sheaths in the distal sciatic nerve, and decreased chromatin accessibility at genomic regions that contain binding motifs for pro-myelinating transcription factors. Our findings suggest that epigenetic-regulated myelin programs perpetuate myelin degradation and drive pathological cold pain. Our improved understanding of the specific mechanisms that maintain myelin degradation during cold hypersensitivity will improve cold pain management, facilitate the completion of cancer treatment, and improve the quality of life for chronic pain patients.

Mora, L. R., Bishop, M. G., Rodriguez, K. A., Redling, D. M., Fox, R., Stephens, K. E.

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